All organisms must maintain homeostasis in the face of changing environmental conditions to survive. Physiological changes associated with ageing decrease the capacity to maintain homeostasis, increasing susceptibility to disease, injury and infection. As a postdoc with Dr. Mark Roth, Dr. Miller found that hydrogen sulfide (H2S), which is naturally produced by animal cells, increases lifespan and thermotolerance in C. elegans. In mammals, H2S improves survival in changing conditions. Thus, H2S may have a conserved function to improve the ability to maintain homeostasis. The purpose ofthe proposed research is to elucidate the mechanistic basis by which H2S modulates lifespan in C. elegans. The first aim will test the hypothesis that H2S delays age-associated changes in C. elegans. These experiments will establish how H2S affects diverse biological processes in different tissue types. In the second aim, genes and pathways involved in the response to H2S will be identified. This work will utilize genetic tools developed by Dr. Miller as a postdoc. Mutant animals which express H2S-induced phenotypes will be characterized to determine whether they influence lifespan and/or other aging-associated phenotypes. Epistasis will be used to determine which act in concert with sir-2.1. In a complementary approach, 1 will evaluate the role of genes that, like sir-2.1, are required for H2S-induced changes. Finally, I will use a microarray approach to identify genes affected by H2S-induced changes and are correlated with increased lifespan. The proposed research will generate publications and preliminary data that will enable Dr. Miller to apply for an independent ROI research award within 24 months of her transition to independence.